This invention is concerned with the field of treatment of proliferative disorders, including malignant and nonmalignant proliferative diseases.
The following information is provided to assist the understanding of the reader, none of that information is admitted to be prior art to the present invention.
The treatment of cancer is one of the most heavily investigated areas in biomedical research today. Although many anticancer drugs have been and continue to be discovered, there remains the immense problem of developing drugs that will be specifically toxic to cancer cells without killing normal cells and causing toxic, often permanent, damage to vital organs or even death. One common measure of the clinical usefulness of any anticancer drugs is its therapeutic index: the ratio of the median lethal dose (LD.sub.50) to the median effective dose (ED.sub.50) of the drug. With some cancer therapeutics this ratio is in the range of 2-4, indicating a high risk of toxic side effects to the patient. Indeed, most anticancer drugs are associated with a high incidence of adverse drug events. The poor therapeutic index of most anticancer drugs not only limit the clinical efficacy of these drugs for the treatment of cancer, but limits their usefulness for treating many non-malignant, proliferative disorders.
A strategy for the development of anticancer agents having a high therapeutic index is described in Housman, International Application PCT/US/94 08473 and Housman, INHIBITORS OF ALTERNATIVE ALLELES OF GENES ENCODING PROTEINS VITAL FOR CELL VIABILITY OR CELL GROWTH AS A BASIS FOR CANCER THERAPEUTIC AGENTS, U.S. Pat. No. 5,702,890, issued Dec. 30, 1997, which are hereby incorporated by reference in their entireties. As further described below, the method involves the identification of genes essential to cell growth or viability which are present in two or more allelic forms in normal somatic cells of a cancer patient and which undergo loss of heterozygosity in a cancer. Treatment of a cancer in an individual who is heterozygous with an allele specific inhibitor targeted to the single allele of an essential gene which is present in a cancer will inhibit the growth of the cancer cells. In contrast, the alternative allele present in non-cancerous cells (which have not undergone loss of heterozygosity) is able to express active product which supplies the essential gene function, so that the normal cells can survive and/or grow.
Cancer cells from an individual almost invariably undergo a loss of genetic material (DNA) when compared to normal cells. Frequently, this deletion of genetic material includes the loss of one of the two alleles of genes for which the normal somatic cells of the same individual are heterozygous, meaning that there are differences in the sequence of the gene on each of the parental chromosomes. The loss of one allele in the cancer cells is referred to as "loss of heterozygosity" (LOH). Recognizing that almost all, if not all, varieties of cancer undergo LOH, and that regions of DNA loss are often quite extensive, the genetic content of deleted regions in cancer cells was evaluated and it was found that genes essential for cell viability or cell growth are frequently deleted, reducing the cancer cell to only one copy. Further investigation demonstrated that the loss of genetic material from cancer cells sometimes results in the selective loss of one of two alleles of a certain essential gene at a particular locus or loci on a particular chromosome.
Based on this analysis, a therapeutic strategy for the treatment of cancer was developed, which will produce agents characterized by a high therapeutic index. The strategy includes: (1) identification of genes that are essential for cell survival or growth; (2) identification of common alternative alleles of these genes; (3) identification of the absence of one of these alleles in cancer cells due to LOH and (4) development of specific inhibitors of the single remaining allele of the essential gene retained by the cancer cell, but not the alternative allele.